Alpha-1 antitrypsin (also known as α1-antitrypsin or A1AT) is a 52 kD serpin glycoprotein produced in hepatocytes and in smaller quantities in phagocytes and lung epithelial cells (Gettins, P. G. Chem. Rev. 2002. 102: 4751-4804). A1AT is a protease inhibitor.
A1AT deficiency (A1ATD) is a genetic disorder associated with the development of liver and lung disease (Bals, R. Best Pract. Res. Clin. Gastroenterol. 2010. 24: 629-633). A1AT deficiency is caused by homozygosity for the A1AT mutant Z gene and occurs in 1 in 2,000 births in many North American and European populations (Teckman, J. H. Semin. Liver Dis. 2007. 27: 274-281). Additionally, recent studies have suggested that the PiZ heterozygous state may be associated with increased severity and worse outcome in liver disease of known etiologies, such as HCV, alcoholic liver disease (ALD) or NAFLD (Regev A. J. Pediatr. Gastroenterol. Nutr. 2006. 43: S30-S35). In the most common genetic deficiency (PiZ, resulting from a mutation of glutamate to lysine at position 342 of the gene), there is accumulation of A1AT in the liver as a result of polymer formation (Stockley, R. A. Expert Opin. Emerg. Drugs. 2010. 15: 685-694). The abnormal mutant protein accumulates within the endoplasmic reticulum of hepatocytes as intrahepatocytic globules. The result of this intracellular accumulation in homozygous ZZ individuals is an increased risk of chronic liver disease and hepatocellular carcinoma (Perlmutter, D. H. et al., Hepatology. 2007. 45: 1313-1323; Teckman, J. H. et al., Curr. Gastroenterol. Rep. 2006. 8: 14-20; Eriksson, S. et al., Am. J. Respir. Crit. Care Med. 2003. 168: 856-869). There are no specific treatments for A1ATD associated liver disease, other than liver transplantation.
A1AT deficiency also predisposes individuals to the development of chronic obstructive pulmonary disease (COPD) and emphysema. In the absence of wild-type A1AT, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory disorders (DeMeo, D. L. and Silverman, E. K. Thorax. 2004. 59: 259-264). Also, in such patients, there is an excess of mutant A1AT polymers, which are bound to the alveolar wall. This enables the polymers to act as a chronic stimulus for neutrophil influx in the lungs of A1AT deficient individuals (Mahadeva, R. et al., Am. J. Pathobiol. 2005. 166: 377-387).
Described herein are compositions and methods for modulating A1AT expression. The compounds and treatment methods described herein provide significant advantages over the treatments options currently available for A1AT-related disorders.